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Endogenous Dendritic Cells from the Tumor Microenvironment Support T-ALL Growth Via IGF1R Activation

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Endogenous Dendritic Cells from the Tumor Microenvironment Support T-ALL Growth Via IGF1R Activation Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation Todd A. Tripletta, Kim T. Cardenasa,1, Jessica N. Lancastera, Zicheng Hua, Hilary J. Seldena, Guadalupe J. Jassoa, Sadhana Balasubramanyama, Kathy Chana, LiQi Lib, Xi Chenc,d, Andrea N. Marcogliesee, Utpal P. Davéf, Paul E. Loveb, and Lauren I. R. Ehrlicha,2 aDepartment of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712; bSection on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; cDivision of Biostatistics, Department of Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136; dSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136; eDepartment of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030; and fDivision of Hematology/Oncology, Tennessee Valley Healthcare System and Vanderbilt University Medical Center, Nashville, TN 37232 Edited by Zena Werb, University of California, San Francisco, CA, and approved January 14, 2016 (received for review October 15, 2015) Primary T-cell acute lymphoblastic leukemia (T-ALL) cells require tumor growth and metastasis (3). Tumor-associated macrophages stromal-derived signals to survive. Although many studies have (TAMs), which resemble alternatively activated (M2) macro- identified cell-intrinsic alterations in signaling pathways that promote phages (4), also support tumor growth. TAMs suppress antitumor T-ALL growth, the identity of endogenous stromal cells and their immune responses, promote tumor invasion and angiogenesis, and associated signals in the tumor microenvironment that support T-ALL are negatively associated with clinical outcomes (5). Macrophage remains unknown. By examining the thymic tumor microenviron- depletion slows tumor progression in multiple cancer models (6–8). ments in multiple murine T-ALL models and primary patient samples, Dendritic cells (DCs) within tumor microenvironments also have we discovered the emergence of prominent epithelial-free regions, aberrant phenotypes and have been implicated in suppression of enriched for proliferating tumor cells and dendritic cells (DCs). antitumor adaptive immune responses (9). Thus, through mitogenic Systematic evaluation of the functional capacity of tumor-associated signaling, tissue remodeling, and suppression of adaptive immunity, stromal cells revealed that myeloid cells, primarily DCs, are necessary heterogeneous cells in the tumor microenvironment cooperate and sufficient to support T-ALL survival ex vivo. DCs support T-ALL to promote growth of solid and hematologic malignancies (2). growth both in primary thymic tumors and at secondary tumor sites. Importantly, human primary T-ALL samples have been shown to To identify a molecular mechanism by which DCs support T-ALL require stromal-derived signals for survival (10). Thus, identifica- growth, we first performed gene expression profiling, which revealed up-regulation of platelet-derived growth factor receptor beta (Pdgfrb) tion of tumor stromal cell types that support T-ALL could unveil and insulin-like growth factor I receptor (Igf1r)onT-ALLcells,with novel therapeutic targets. concomitant expression of their ligands by tumor-associated DCs. There is ample reason to suspect that the thymic microenviron- Both Pdgfrb and Igf1r were activated in ex vivo T-ALL cells, and co- ment, the primary site of T-ALL, contributes to lymphomagenesis. culture with tumor-associated, but not normal thymic DCs, sustained IGF1R activation. Furthermore, IGF1R signaling was necessary for DC- Significance mediated T-ALL survival. Collectively, these studies provide the first evidence that endogenous tumor-associated DCs supply signals driv- T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of ing T-ALL growth, and implicate tumor-associated DCs and their mi- developing T cells. Cancer cell growth is often driven by cell- togenic signals as auspicious therapeutic targets. intrinsic alterations in signaling pathways as well as extrinsic signals from the tumor microenvironment. Here we identify T-ALL | leukemia | dendritic cell | tumor microenvironment | IGF1R tumor-associated dendritic cells as a key endogenous cell type in the tumor microenvironment that promotes murine T-ALL -cell acute lymphoblastic leukemia (T-ALL) is an aggressive growth and survival at both primary and metastatic tumor sites. Tmalignancy of T-cell progenitors that predominantly affects We also find that tumor-associated dendritic cells activate the in- children and adolescents. Intensified chemotherapeutic regimens sulin-like growth factor I receptor in T-ALL cells, which is critical for have improved 5-y event-free survival rates to over 75% in children their survival. Analysis of primary patient T-ALL samples reveals and 50% in adults. However, these therapies are toxic, and patients phenotypically analogous tumor microenvironments. Our findings who fail to respond or relapse have poor outcomes (1). The main suggest that targeting signals from the tumor microenvironment focus of T-ALL research has been identification of cell-intrinsic could expand therapeutic options for T-ALL. genetic permutations that promote tumor growth, such as activating mutations in the transcription factor NOTCH1,deletionoftumor Author contributions: T.A.T., K.T.C., and L.I.R.E. designed research; T.A.T., K.T.C., J.N.L., suppressor genes in the CDKN2A locus, and aberrant activation of H.J.S., G.J.J., S.B., and K.C. performed research; L.L., A.N.M., U.P.D., and P.E.L. contributed new reagents/analytic tools; T.A.T., K.T.C., J.N.L., Z.H., K.C., X.C., and L.I.R.E. analyzed transcriptional regulators such as LIM domain only 2 (LMO2)(1). data; and T.A.T. and L.I.R.E. wrote the paper. Despite our understanding of these common cell-intrinsic alterations, The authors declare no conflict of interest. we have yet to develop successful, targeted therapeutic approaches to This article is a PNAS Direct Submission. improve patient outcomes, suggesting that we need to broaden our Data deposition: The transcriptional profiling data reported in this paper have been de- understanding of other factors promoting T-ALL growth (1). posited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo Tumor progression is driven not only by cell-intrinsic alter- (accession no. GSE54609). ations but also by dynamic interactions between cancer cells 1Present address: Department of Molecular Medicine, University of Texas Health Science and the surrounding tumor microenvironment (2). For example, Center at San Antonio, San Antonio, TX 78240. cancer-associated fibroblasts (CAFs) secrete factors that pro- 2To whom correspondence should be addressed. Email: [email protected]. mote tumor survival, angiogenesis, and recruitment of inflamma- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. tory cells. CAFs also mediate tissue remodeling that promotes 1073/pnas.1520245113/-/DCSupplemental. E1016–E1025 | PNAS | Published online February 9, 2016 www.pnas.org/cgi/doi/10.1073/pnas.1520245113 Downloaded by guest on September 27, 2021 Normal thymocytes must engage in bidirectional signaling with het- PNAS PLUS erogeneous thymic stromal cells to promote proper differentiation of both thymocyte and stromal compartments (11, 12). Thymic stromal cells consist of hematopoietic cells, such as DCs and macrophages, and nonhematopoietic cells, such as thymic epithelial cells (TECs) and fibroblasts. Thymocyte:TEC crosstalk is essential at multiple stages of T-cell development. TECs express NOTCH ligands and IL-7, which are required for differentiation of normal T-cells (13–15), buthavealsobeenimplicatedinT-ALLtumorigenesis(10,16).Thus, nascent lymphoma cells may coopt signals in the thymic microenvi- ronment to promote tumor growth. Previous studies demonstrated that stromal support is required for ex vivo survival of mouse and human T-ALL cells (10, 17–20) and implicated IL-7 and NOTCH1 signaling in promoting tumor survival (10, 16–18). Together, these findings suggest that TECs might promote T-ALL. However, the above studies addressed the role of stroma in supporting T-ALL predominantly using cell lines and exogenous cytokines; thus, the contribution of endogenous stromal cells in the T-ALL tumor mi- croenvironment remains largely unexplored. Herein, we identify primary stromal cells from the endogenous tumor microenvironment that support T-ALL growth ex vivo. Our data reveal that DCs are expanded within primary and metastatic Fig. 1. LN3 thymic T-ALL cells require tumor stroma to survive and pro- liferate ex vivo. (A) Survival of indicated strains shown as Kaplan–Meier T-ALL tumor microenvironments. Despite the essential contribution survival plots (n = 33, WT; n = 155, LN3). (B–E) Primary T-ALL cells were of TECs to normal thymocyte development, TECs are dispensable cultured with or without stromal cells enriched from mechanically dissoci- for T-ALL survival in tumor:stromal cocultures. In contrast, myeloid ated LN3 thymic tumors or WT thymi. Representative flow cytometric plots cells, particularly DCs from tumor microenvironments at both pri- evaluating viability (B) or DNA content (D) of viable cells 6 d after culture mary and secondary tumor sites, are necessary and sufficient to initiation. (C and E) The percentage of viable
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